Parkinson's disease (PD) is an important public health problem for older Americans. Although dramatic advances have been made in the clinical management of PD, the mechanisms that underlie its neurodegeneration are incompletely understood. It is necessary to understand these mechanisms in order to design effective procedures and therapeutic approaches to prevent the development or to impede the progression of PD. The long-term objectives of this project are to determine the mechanisms by which dithiocarbamate (DTC)-based pesticides linked to PD epidemiologically contribute to dopaminergic neurodegeneration in PD. The specific aims of this project are: (1) to determine structure- activity relationships of DTCs in vitro as mitochondrial and dopaminergic neurotoxins, and in vivo as dopaminergic neurotoxins after exposure to systemically administered DTCs in young and old wild type mice as well as mice with genetically altered anti-oxidant defenses, (2) to determine structure-activity relationships of systemically administered DTCs as inducers of oxidative stress in different brain regions that have either significant or minimal neurodegeneration in PD in wild type mice and mice with genetically altered antioxidant defenses, (3) to assess mechanisms of oxidative stress and the effects of oxidative stress on excitotoxicity in different brain regions that have either significant or minimal neurodegeneration in PD in rats exposed to DTCs directly through brain microdialysis. The new information will shed more light on the mechanisms by which pesticides interact with aging and genetic vulnerability thereby contributing to development and progression of PD.